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Deng et al. (Science 355, 1173, 2017) described the role uridine plays on thermoregulation and glucose sensitivity. The suggestion that an adipo-biliary-uridine axis is behind this novel physiological regulatory mechanism is particularly exciting. These authors discuss about how uridine is transported in this system, focusing on hepatocytes and bile tract and cite several studies from our laboratory. In order to make some points clearer I would like to comment on this topic. The authors mention that whereas CNT1- and CNT2-related proteins are responsible for the concentrative Na-dependent high-affinity transport of pyrimidine, less is known about the transport of uridine. In fact, whereas CNT1 is a pyrimidine nucleoside transporter, CNT2 is a purine-preferring nucleoside transporter, exceptionally translocating uridine despite being a pyrimidine. And this is indeed the case for the whole set of plasma membrane nucleoside transporter proteins (CNT1, CNT2, CNT3, ENT1, ENT2), because they all bind and translocate uridine although with different affinity (1). Thus, the major players in uridine uptake by cells are well known. They also mention that their data suggest the presence of nucleoside carriers on both canalicular and sinusoidal membranes of hepatocytes. Indeed, the polarized distribution of nucleoside transporters in hepatocytes is also known and reflects quite an atypical pattern for an epithelial cell, expressing CNT1 and CNT2 at both membrane domains(2). Evidence su...

Deng et al. (Science 355, 1173, 2017) described the role uridine plays on thermoregulation and glucose sensitivity. The suggestion that an adipo-biliary-uridine axis is behind this novel physiological regulatory mechanism is particularly exciting. These authors discuss about how uridine is transported in this system, focusing on hepatocytes and bile tract and cite several studies from our laboratory. In order to make some points clearer I would like to comment on this topic. The authors mention that whereas CNT1- and CNT2-related proteins are responsible for the concentrative Na-dependent high-affinity transport of pyrimidine, less is known about the transport of uridine. In fact, whereas CNT1 is a pyrimidine nucleoside transporter, CNT2 is a purine-preferring nucleoside transporter, exceptionally translocating uridine despite being a pyrimidine. And this is indeed the case for the whole set of plasma membrane nucleoside transporter proteins (CNT1, CNT2, CNT3, ENT1, ENT2), because they all bind and translocate uridine although with different affinity (1). Thus, the major players in uridine uptake by cells are well known. They also mention that their data suggest the presence of nucleoside carriers on both canalicular and sinusoidal membranes of hepatocytes. Indeed, the polarized distribution of nucleoside transporters in hepatocytes is also known and reflects quite an atypical pattern for an epithelial cell, expressing CNT1 and CNT2 at both membrane domains(2). Evidence supporting a positive regulation of CNT2 function by bile acids was indeed published by our group but data were reported in (3). Interestingly, our laboratory also identified the major players implicated in nucleoside transport in cholangiocytes (4), which for sure should be implicated in determining the efficacy of biliary uridine loss, considering all nucleoside transporters identified in cholangiocytes are able to translocate uridine. A better knowledge of this regulatory axis will require a re-evaluation of the role membrane transporters play in modulating uridine metabolism, both at the organ and whole animal level.